ORIGINAL RESEARCH article
Front. Psychiatry
Sec. Addictive Disorders
Volume 16 - 2025 | doi: 10.3389/fpsyt.2025.1594313
Integrated Metabolomic-Lipidomic Profiling Reveals Novel Biomarkers and Therapeutic Targets for Alcohol Use Disorder with Cognitive Impairment
Provisionally accepted
- 1College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
- 2Department of Psychiatry, Second People's Hospital of Hunan Province, Changsha, Hunan Province, China
- 3Changsha Central Hospital, Changsha, Hunan Province, China
- 4Jiangxi Provincial People's Hospital, Nanchang, Jiangxi Province, China
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Purpose: Alcohol use disorder (AUD) is a chronic relapsing condition frequently complicated by cognitive impairment (CI), yet its underlying metabolic mechanisms remain poorly understood. This study aimed to identify plasma metabolic signatures and dysregulated pathways associated with AUD-CI using an integrated multi-omics approach.: A prospective cohort study of 210 male participants (70 AUD-CI, 70 AUD without CI [AUD-NonCI], and 70 healthy controls [HCs]) was conducted. Plasma samples underwent LC-MS/MS-based metabolomic and lipidomic profiling. Cognitive function was assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). Machine learning algorithms (Random Forest and LASSO regression) were employed for biomarker selection, and pathway analysis was performed using MetaboAnalyst 5.0. Results: The multi-omics platform detected 117 differentially expressed molecules (11 metabolites and 106 lipids) with high diagnostic accuracy (mean AUC=0.92±0.03). Key findings included depletion of S-adenosylmethionine (SAM; 1.8-fold decrease, p=3.4×10⁻⁴) and accumulation of ceramide species Cer (d18:1/26:2) (2.1-fold increase, p=7.8×10⁻⁴). Pathway analysis revealed mTORC1 signaling (p=1.4 ×10⁻⁴) and sphingolipid metabolism (p=2.1×10⁻⁵) as central dysregulated pathways. AUD-CI patients exhibited 49 unique lipid alterations, notably 70% reduction of phosphatidylcholine PC (42:4) versus HCs (p=0.002), strongly correlated with synaptic protein markers (r=0.82, p<0.001). Conclusion: Our findings characterize a dysregulated liver-gut-brain metabolic axis in AUD-CI pathogenesis, highlighting the mTORC1-sphingolipid pathway as a promising therapeutic target. The identified biomarkers provide mechanistic insights into alcoholinduced neurotoxicity, offering potential avenues for precision interventions in AUDrelated cognitive decline.
Keywords: alcohol use disorder, cognitive impairment, Metabolomics, lipidomics, Sphingolipid metabolism, mTORC1 pathway
Received: 15 Mar 2025; Accepted: 21 May 2025.
Copyright: © 2025 Li, Chen, Zhou, Yang, Ou and Zhou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Xuhui Zhou, College of Integrated Traditional Chinese and Western Medicine, Hunan University of Chinese Medicine, Changsha, China
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